Constitutively active homo-oligomeric angiotensin II type 2 receptor induces cell signaling independent of receptor conformation and ligand stimulation
Constitutively active homo-oligomeric angiotensin II type 2 receptor induces cell signaling independent of receptor conformation and ligand stimulation
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DOI：
10.1074/jbc.m500639200
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发表时间：
2005-05-06
影响因子：
4.8
通讯作者：
Saku, K
中科院分区：
文献类型：
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作者：
Miura, S;Karnik, SS;Saku, K
G蛋白偶联受体超家族（GPCR）的成员经历同源和/或异源寡聚化以诱导细胞信号传导。尽管其中一些显示出组成性激活，但尚不清楚此类GPCR如何经历同源寡聚化与跨膜螺旋运动。血管紧张素Ⅱ（Ang Ⅱ）2型（AT（2））受体是一种GPCR，其组成性激活和诱导凋亡不依赖于其配体Ang Ⅱ。在本研究中，我们分析了AT（2）受体在诱导细胞信号转导时的跨膜运动的易位和寡聚化。组成型活性同源寡聚化是由于一个AT（2）受体中的Cys（35）和另一个AT（2）受体中的Cys（290）之间的二硫键连接所致，其在没有Ang II刺激的情况下定位于细胞膜，并诱导细胞凋亡而不改变受体构象。这些结果提供了直接的证据，即组成型活性的同源寡聚GPCR通过两个细胞外环中的分子间相互作用易位到细胞膜并诱导细胞信号传导，而不依赖于受体构象和配体刺激。
Members of the G-protein-coupled receptor superfamily (GPCRs) undergo homo- and/or hetero-oligomerization to induce cell signaling. Although some of these show constitutive activation, it is not clear how such GPCRs undergo homo- oligomerization with transmembrane helix movement. We previously reported that angiotensin II (Ang II) type 2 (AT(2)) receptor, a GPCR, showed constitutive activation and induced apoptosis independent of its ligand, Ang II. In the present study, we analyzed the translocation and oligomerization of the AT(2) receptor with transmembrane movement when the receptor induces cell signaling. Constitutively active homo- oligomerization, which was due to disulfide bonding between Cys(35) in one AT(2) receptor and Cys(290) in another AT(2) receptor, was localized in the cell membrane without Ang II stimulation and induced apoptosis without changes in receptor conformation. These results provide the direct evidence that the constitutively active homo- oligomeric GPCRs by intermolecular interaction in two extracellular loops is translocated to the cell membrane and induces cell signaling independent of receptor conformation and ligand stimulation.